20-54154057-G-C

Variant names:

• chr20-54154057-G-C
• rs6022987
• NM_000782.5:c.*715C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000782.5(CYP24A1):​c.*715C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 151,540 control chromosomes in the GnomAD database, including 5,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: CYP24A1 NM_000782.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.836
• Publications: 7 publications found

Genes affected

CYP24A1 (HGNC:2602): (cytochrome P450 family 24 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein initiates the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D3, by hydroxylation of the side chain. In regulating the level of vitamin D3, this enzyme plays a role in calcium homeostasis and the vitamin D endocrine system. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP24A1 Gene-Disease associations (from GenCC):

• hypercalcemia, infantile, 1

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• autosomal recessive infantile hypercalcemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286587 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-54154057-G-C is Benign according to our data. Variant chr20-54154057-G-C is described in ClinVar as Benign. ClinVar VariationId is 338797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP24A1	NM_000782.5	c.*715C>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000216862.8	NP_000773.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP24A1	ENST00000216862.8	c.*715C>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_000782.5	ENSP00000216862.3

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39884 AN: 151416 Hom.: 5753 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.263 AC: 39928 AN: 151536 Hom.: 5759 Cov.: 32 AF XY: 0.268 AC XY: 19816 AN XY: 74014

African (AFR) AF: 0.166 AC: 6840 AN: 41268

American (AMR) AF: 0.224 AC: 3409 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3464

East Asian (EAS) AF: 0.103 AC: 530 AN: 5144

South Asian (SAS) AF: 0.327 AC: 1574 AN: 4808

European-Finnish (FIN) AF: 0.387 AC: 4056 AN: 10480

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21499 AN: 67838

Other (OTH) AF: 0.268 AC: 564 AN: 2106

Alfa AF: 0.180 Hom.: 390

Bravo AF: 0.241

Asia WGS AF: 0.236 AC: 823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercalcemia, infantile, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.15
DANN	Benign	0.68
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6022987; hg19: chr20-52770596;